Transmethylation of cellular constituents has been associated with several diseased states; e.g., biogenic amines and schizophrenia. A detailed knowledge of the chemical mechanism by which such processes take place should allow us to design drugs that could block the transmethylation pathway(s) of interest. During the current period of support (04-06 yr.) we have succeeded in elucidating the detailed mechanism by which transalkylation reactions of sulfonium compounds are effected, and have developed potent new inhibitors of methylases which are active in isolated enzyme systems, and in whole cells. During the coming period of support (07-09 yr.) we plant to continue those studies on the mechanism by which sulfonium compounds (e.g., S-adenosylmethionine) participate in transalkylation reactions, and to extend our initial studies on the mechanistic aspects of transmethylation involving 5-methyltetrahydrofolate (and its oligoglutamate conjugates). We wish to continue our approach of using non-enzymic mechanistic studies, combined with kinetic and spectral probes of enzyme mechanism, to provide a rational basis for the design of inhibitors specific for a particular methylase; e.g., catechol-O-methyltransferase. These highly specific inhibitors will then be investigated for possible use as drugs in the treatment of diseases associated with the transmethylation processes.